history and trends in bioprocessing and biotransformation - t. scheper, n. n. dutta, f. hammar

Advances in Biochemical Engineering/
Biotechnology,Vol. 75
Managing Editor: Th. Scheper
© Springer-Verlag Berlin Heidelberg 2002
History of Modern Genetics in Germany
Friederike Hammar
Institute for Physiological Chemistry, Johannes-Gutenberg-University, 55099 Mainz, Germany,
e-mail:
The history of modern genetics in Germany during the 20th century is a story of missed
chances. In the USA the genetic revolution opened a fascinating new field for ambitious scien-
tists and created a rapidly growing new industry. Meanwhile Germany stood aside, combating
with political and social restrictions. Promising young scientists who wanted to work in the
field left Germany for the US, and big companies moved their facilities out of the country. Up
until the middle of the 1990s molecular biology in Germany remained a “sleeping beauty”even
though many brilliant scientists did their jobs very well. Then a somewhat funny idea changed
everything: the German minister for education and science proclaimed the BioRegio contest in
order to award the most powerful biotechnology region in Germany concerning academia and
especially industry. Since then Germany’s biotechnology industry has grown constantly and
rapidly due to the foundation of a number of small biotech companies; big companies have re-
turned their interests and their investments to Germany, paralleled by an improvement in aca-
demic research because of more funding and better support especially for younger scientists.
In respect to biotechnology and molecular biology, Germany is still a developing country, but
it has started to move and to take its chances in an exciting global competition.
Keywords. History, Molecular genetics, Biotech industry, Genomics, Proteomics
1Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1 The Birth of Modern Genetics . . . . . . . . . . . . . . . . . . . . . 2
1.2 Molecular Genetics Grows Up . . . . . . . . . . . . . . . . . . . . . 4
1.3 Sequencing the Human Genome . . . . . . . . . . . . . . . . . . . 5
1.4 The Max Planck Society . . . . . . . . . . . . . . . . . . . . . . . . 6
2 The 1970s: The ‘First Genetic Revolution’ – and Germany? . . . . . 8

2.1 The Max Delbrück Center in Berlin-Buch . . . . . . . . . . . . . . 9
2.2 The German Center for Cancer Research in Heidelberg . . . . . . 10
2.3 The European Molecular Biology Laboratory in Heidelberg . . . . 10
3 The 1980s: Molecular Genetics Struggling Against Political Forces 11
3.1 Hoechst and Insulin – A Never-Ending Story . . . . . . . . . . . . 12
4 The 1990s: A New Beginning – ‘The Second Genetic Revolution’ . . 13
4.1 Developing a German Biotech Industry . . . . . . . . . . . . . . . 14
4.1.1 Qiagen – The Pioneer . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1.2 Rhein-Biotech – Becoming a Global Player . . . . . . . . . . . . . . 14
4.1.3 MWG-Biotech – An Instrumentation Supplier Develops into
a Genomics Company . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.1.4 Evotec – Molecular Evolution for Drug Screening . . . . . . . . . . 15
4.2 The BioRegio Contest – Gambling for Success . . . . . . . . . . . . 15
4.3 Germany’s Contribution to the Human Genome Project
and Other Genome Projects . . . . . . . . . . . . . . . . . . . . . . 16
4.3.1 DHGP – German Human Genome Project . . . . . . . . . . . . . . 17
4.3.1.1 Milestones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.3.2 Microbial Genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5 After 2000: Starting the Biological Age . . . . . . . . . . . . . . . . 23
5.1 Beyond the Genome – Functional Genomics and Proteomics . . . 23
5.2 Ethical, Legal and Social Implications of Genomic Research . . . . 25
5.2.1 Patents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6 Further Perspectives: ‘Green’ Biotechnology . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Abbreviations
BMBF Federal Ministry of Education and Research
DFG German Research Association
DGHP German Human Genome Project
DKFZ German Center for Cancer Research
EMBL European Molecular Biology Laboratory

GBF Gesellschaft für Biologische Forschung – Society for Biological
Research
GDR German Democratic Republic
IMB Institute of Molecular Biology
KWS Kaiser Wilhelm Institute
MDC Max Delbrück Center
MPI Max Planck Institute
MPS Max Planck Society
PCR polymerase chain reaction
SAGE serial analysis of gene expression
TIGR The Institute of Genomic Research
1
Introduction
1.1
The Birth of Modern Genetics
From a biologist’s point of view, the 20th century can be named the ‘century of
genetics’: starting with the rediscovery of the Mendelian laws by Carl Erich
2 F. Hammar
Correns (Berlin), Erich von Tschermak (Vienna) and Hugo de Vries
(Amsterdam) in 1900 [1]. Mendel’s rules, originally formulated in 1866, postu-
late that different genetic traits are inherited independently. In 1902 Walter
Stanborough Sutton observed chromosomal movements during meiosis and de-
veloped the chromosomal theory of heredity. He stated that the chromosomes
are the carriers of Mendel’s ‘factors’ of heredity. Sutton gave these factors the
name we still use today: he called them ‘genes’. In 1903 Sutton and Theodor
Boveri working independently suggested that each germ cell contains only one
half of each chromosome pair. In 1905, Edmund Wilson and Nellie Stevens pro-
posed the idea that separate X and Y chromosomes determine sex.Thomas Hunt
Morgan started experiments with the fruit fly Drosophila melanogaster in 1910
and proved that certain genes are linked to each other and that linked genes can

be exchanged by a mechanism called crossing over [2,3].Based on these results,
Alfred Sturtevant was able to draft the first genetic maps to locate the genes on
the chromosomes in 1913 [4].Herman Müller, who also worked in Morgan’s lab-
oratory, performed the first experiments to produce mutations by radioactive
radiation. In 1927 he was able to demonstrate that X-rays cause a high rate of
mutations [5]. These experiments, A. E. Garrod’s observation of inherited dis-
eases like phenylketonuria [6] and later the work of George Beadle and Edward
Tatum on the fungus Neurospora crassa, showed the relationship between genes
and enzymes and led to the formulation of the ‘one-gene-one-enzyme’ hypo-
thesis in 1941 [7, 8].
However, until 1944, nothing was known about the nature of the substance
building the genes. Then Oswald Avery was able to show that nucleic acids are
the molecules that constitute the genes [9] – a result that was regarded with
suspicion by the greater part of the scientific community who favored proteins
because of their greater complexity. They doubted that a molecule as simple as
DNA could perform the complex tasks of processing genetic information. But
Avery’s experiments had an enormous influence on the work of Erwin Chargaff,
an Austrian scientist who had emigrated to the USA in 1934. He demonstrated
that in every nucleic acid the numbers of the nucleo-bases adenine and thymine
are equal as well as the numbers of the bases guanine and cytosine [10].This was
the first hint to elucidate the base-pairing in a DNA molecule and it determined
the work of James Watson and Francis Crick. In 1953 they were able to deduce a
model for the structure of DNA from the crystallographic pictures provided by
Rosalind Franklin [11–13].
Two other scientific personalities greatly influenced the early steps of molecu-
lar genetics: Max Delbrück, a German physicist who went to the USA in 1937 and
the chemist Linus Pauling. Together they developed a theory to explain the com-
plementary interaction of biological molecules using weak binding forces like hy-
drogen bonds [14]. Max Delbrück was one of the pioneers of bacterial genetics.
He and his co-worker Salvador Luria developed the first quantitative test to study

mutations in bacteria [15]. They also invented a simple model system using
phage to study how genetic information is transferred to host bacterial cells.
Moreover they organized courses on phage genetics that attracted many scien-
tists to Cold Spring Harbor, which soon became an interesting and exciting cen-
ter for new ideas about explaining heredity at the molecular and cellular level.
History of Modern Genetics in Germany 3
1.2
Molecular Genetics Grows Up
As the field of molecular genetics grew, the DNA molecule became the focus of
many research efforts.Francis Crick and George Gamov developed the ‘sequence
hypothesis’ to explain how DNA makes protein. They stated that the DNA se-
quence specifies the amino acid sequence of a protein and postulated the central
dogma of molecular genetics: the flow of genetic information is a one-way road,
it always takes the direction from DNA to RNA to protein [16]. In the same year,
1957, Mathew Meselson and Frank Stahl demonstrated the replication mecha-
nism of DNA [17]. In 1958, DNA polymerase became the first enzyme used to
make DNA in a test tube.
The work of Marshal Nirenberg and Heinrich Matthaei between 1961 and
1966 resulted in the cracking of the genetic code [18]. They demonstrated that a
codon consisting of three nucleotide bases determines each of the 20 amino
acids.
In 1967, the enzyme DNA ligase was isolated. DNA ligase binds together
strands of DNA. Its discovery, together with the isolation of the first restriction
enzyme in 1970, paved the way for the first recombinant DNA molecules to be
created by Paul Berg in 1972. In doing so, he created the field of genetic engi-
neering. However, upon realizing the dangers of his experiment, he terminated
it before it could be taken any further. He immediately, in what is now called the
‘Berg Letter’, proposed a 1-year moratorium on recombinant DNA research, in
order for safety concerns to be worked out.These safety concerns were later dis-
cussed by molecular biologists at a conference in Asilomar in 1975 – a unique

event in the history of the sciences.This concern of the scientific community re-
flects the attitude of the general public: until today, molecular biology and
genetic engineering are at least in part regarded with suspicion and mistrust
by a large part of the population not only in Germany but also in Great Britain
and other countries.
In 1973 Cohen and Boyer combined their research efforts to produce the first
recombinant DNA organisms: cells of the bacterium E. coli. Cohen and Boyer’s
implementation of the technique laid the foundations for today’s modern genetic
engineering industry. As a logical consequence, Herbert Boyer together with
Robert Swanson,a young visionary venture capitalist, established the first
Biotechnology Company: Genentech was founded in 1976. As soon as 1977
Genentech reported the production of the first human protein – Somatostatin –
manufactured in a bacteria [19].In the USA the ‘Age of Biotechnology’had begun.
In the following 20 years most of the major inventions in molecular genetics
were not made in Germany. In 1977,Walter Gilbert and Allan Maxam devised a
method for chemically sequencing DNA [20, 21]. In 1983 Kary Mullis developed
the polymerase chain reaction (PCR) [22, 23]. This technique allows for the
rapid synthesis of DNA fragments. In about an hour, over 1 million copies of a
DNA strand can be made.The technique has been invaluable to the development
of biotechnology and genetic engineering.
The first transgenic animals were produced in 1981 at Ohio University [24]
and the technical developments towards powerful and efficient automated DNA
4 F. Hammar
sequencing machines took place in the USA. In 1996 Ian Wilmut and Keith
Campbell, researchers at the Roslin Institute in Scotland, created Dolly, the first
organism ever to be cloned from adult cells [25–27]. A consolation for German
scientists may be the fact that one of the pioneers of cloning was a German em-
bryologist: In 1928 Hans Spemann performed the first nuclear transfer experi-
ment with salamander embryo cells.
1.3

Sequencing the Humane Genome
About 10 years ago the scientific community felt that automation techniques for
sequencing genes and the supporting computers and software were at a state to
start one of the most challenging scientific projects: In October of 1990, the
National Institutes of Health officially began the Human Genome Project,a mas-
sive international collaborative effort to locate the estimated 30,000 to 100,000
genes and sequence the 3 billion nucleotides making up the entire human
genome.By determining the complete genetic sequence,scientists hope to begin
correlating human traits with specific genes. With this information, medical re-
searchers have begun to determine the intricacies of human gene function, in-
cluding the source of genetic disorders and diseases that have plagued medical
researchers for years. To date more than 200 genes predisposing for diseases
have been analyzed, e.g. Parkinson’s disease [28], breast cancer [29], prostrate
cancer [30] and Alzheimer’s disease [31].
In planning the project, research was divided among various American uni-
versities. The $3-billion project was scheduled for completion in 2005, but there
were doubts whether this deadline would be made. After 5 years of considering
the pros and the cons Germany finally joined the Human Genome Project in
1995. The German Ministry for Research and Education is supporting the
German Human Genome Project (DGHP) until 2003 with 200 million German
Marks.
In January of 1998, the biotechnology firm Perkin-Elmer Corp. announced
that it was teaming up with gene-sequencing expert J. Craig Venter to privately
map the human genome.Perkin-Elmer plans to use brand new gene-sequencing
technology to completely map all human DNA by the year 2001 for an estimated
cost of $150–200 million dollars. Venter had proposed a new approach for se-
quencing the human genome with shotgun techniques, an idea regarded with
skepticism by his colleagues. As he was not able to raise public funding for his
idea,he offered it to Perkin-Elmer who was soon convinced to give him a try and
supported the foundation of Celera Genomics to perform the task.

The competition among the private and the public initiatives accelerated the
human genome project dramatically. Already in June 2000, 5 years ahead of the
public prospect and even 1 year in advance of his own proposal,Craig Venter an-
nounced the completion of the human genome sequence. One of the most im-
portant milestones of genetic research had been achieved.
Even though German scientists had much influence on the emerging disci-
pline of ‘molecular genetics’, the greatest part of the development took place in
America and not in Germany. Max Delbrück, for example, one of the ‘fathers’ of
History of Modern Genetics in Germany 5
molecular biology, started his career at the former Kaiser Wilhelm Institute in
Berlin (see Table 1). In 1932 he – like many other German scientists – left
Germany for well-known political reasons and did not return after World War II
was over; with one exception: when he helped to establish the Max Planck
Institute for molecular genetics at the university of Cologne, which was opened
in1962.
In the 1970s and 1980s German scientists were also working at the cutting
edge of modern molecular biology.But similar to Axel Ulrich or Peter Seeburg –
both now directors of Max Planck Institutes in Munich and Heidelberg, respec-
tively – who were researchers at Genentech in the early years of the company,
many of them had left their home country because political restrictions and un-
friendly public opinion limited the possibilities for researchers especially in the
biological sciences in Germany.
What were the reasons for the hesitant progress of modern genetics in
Germany after World War II? The reconstruction of the Max Planck Society
(MPS) on the ruins of the former Kaiser Wilhelm Institutes reflects the develop-
ment of research and technology in general and of molecular genetics in partic-
ular,in relation to public and political support.
1.4
The Max Planck Society
The Max Planck Society for the Advancement of the Sciences (MPS) is an inde-

pendent, non-profit research organization. It was established on February 26,
1948, as the successor organization of the former Kaiser Wilhelm Society. Max
Planck Institutes conduct basic research in service to the general public in the
areas of natural science, social science and the arts and humanities.
Following the collapse of the Third Reich, for German science, as for many
sectors of public life, the need for a new start was essential. The state of
Germany’s institutions at the end of the war corresponded to the general chaos
accompanying the defeat. The various institutes of the Kaiser Wilhelm Society
(KWS) originally founded in 1911, the predecessor of the Max Planck Society,
were damaged or housed provisionally at different evacuation sites.The years of
6 F. Hammar
Table 1. Curriculum vitae of Max Delbrück
– 1906 born in Berlin
– 1930 Ph.D.Göttingen, theoretical physics (quantum mechanics) in the group of Max Born
– 1930–1932 postdoctoral years in England, Switzerland and Denmark, contact with
Wolfgang Pauli and Niels Bohr
– 1932 Berlin, to work with Otto Hahn and Lise Meitner
– 1937 fellowship of the Rockefeller Foundation to Caltech, work with Emory Ellis
– 1940 instructor of physics,Vanderbilt University
– 1947 Caltech, cooperation with Salvador Luria, establishment of the ‘Phage Group’
– from 1950 work on Phycomyces
– 1956 helps to set up the Institute of Molecular Genetics at the University of Cologne
– 1969 Nobel Prize in Physiology and Medicine
– 1981 died in the USA
the National Socialist dictatorship had left doubts as to the moral integrity of the
internationally renowned scientific organization. Several KWS institutes had
been pressed into service for military research tasks during the war and indi-
vidual scientists had broken the fundamental ethical rules of science. The orga-
nization of the KWS had during the years of National Socialist government lost
its independence and its moral reputation. Therefore, many scientists of the de-

structed KWS thought that a new beginning was absolutely necessary. Parallel to
the construction of the federal government, the MPS emerged from the ruins of
the KWS due to the initiatives of individual institutes and their scientists. The
months of struggle for survival as a research organization after the end of World
War II were followed by years of striving to ensure a financial basis for the MPS.
The MPS was, from the very beginning, dependent on public funding. In accor-
dance with the federal structure, the responsibility of providing the MPS with
basic financial means fell at first solely to the individual German states, with re-
spect to their sovereignty in cultural matters. Since the MPS spoke with one
voice for the entirety of its institutes, the states were obliged to coordinate their
efforts to ensure financial backing. On March 24, 1949, even before the estab-
lishment of the Federal Republic itself, the cultural and finance ministers of 11
states and West Berlin agreed upon a ‘National Act for the Funding of Scientific
Research Facilities’, the so-called ‘Königstein Act’, a financial arrangement
which codified the common and sole responsibility of the individual states con-
cerning the financial furthering of research and recognized the necessity of a
permanent institutional funding for research facilities such as the Max Planck
Society as a national obligation.
The 1950s were years in which the first steps towards a limited scientific re-
structuring could be undertaken. For instance, the MPS addressed itself to new
research topics,such as behavioral psychology,chemistry of cells,aeromony and
astrophysics,nuclear or plasma physics,or concentrated on issues already being
pursued such as virus research or physical chemistry.Scientific cooperation be-
yond Germany’s borders was extended step by step. Particularly high expecta-
tions accompanied the establishment of contacts between scientists of the MPS
and those of Israel’s Weizmann Institute in 1959.
The 1960s meant an unparalleled phase of upswing and further scientific de-
velopment for the MPS.Within 6 years the number of research installations rose
to 52.At the beginning of the 1970s the MPS had 8000 employees, of whom 2000
were scientists. With the number of new establishments and the extension of

sectional structures in the institutes, the number of directorial staff doubled.
These years witnessed the rise of new large research centers of international di-
mensions in biochemistry, biophysical chemistry, molecular genetics, immune
biology, biological cybernetics and cellular biology. New, elaborate research en-
deavors in physics and chemistry of interdisciplinary character were launched.
The decision to establish new institutes in the 1960s was still making a profound
effect at the beginning of the 1970s. From the middle of the 1970s, however, the
MPS suddenly found itself staggering under the burden of stagnating budgets.
Even if previous new research topics were taken up in these years, this was only
possible through shifting of internal priorities and reshuffling. The Society
could no longer count on further expansion.The founding of new institutes was
History of Modern Genetics in Germany 7
only possible through the renaming or shutting down of entire institutes in
other locations. The restructuring and thematic shift of emphasis affecting
whole institutes on the occasion of a director taking his leave assumed major
importance. Sustaining research under conditions of stagnating budget became
the first great challenge. In the interim between 1972 and 1984, 20 institutes
and/or sections were shut down.New forms of research promotion,such as tem-
porary research groups,especially in the area of clinical research, as well as pro-
ject groups, were introduced; participation in large-scale research projects in-
creased. Eleven institutes, in part emerging from project groups, were founded.
In the Biology-Medicine section the sectors endocrinology, neurology, psychol-
ogy and psycholinguistics came to the fore,while labor physiology and virus re-
search received a new orientation towards system physiology or developmental
biology. In the 1970s the Max Planck Society expanded its international activi-
ties even further.
Only towards the end of the 1980s was a breakthrough achieved in the finance
question.In December, 1989, the governing parties at the federal and state levels
gave an unmistakable demonstration of their support for a preferred promotion
of scientific excellence and financial security of future planning for that leading

organization in the area of pure research. Even though no new posts were as-
signed, it was again possible to provide every German state with at least one Max
Planck Institute. In the 1990s the unification of the two German states appeared
on the horizon.At the same time the accelerated process of European unification
placed German research configurations under pressure to adapt. For the MPS,
German unification meant both challenge and opportunity [32]. The MPS
aimed to construct 20 institutes, whose quality as international centers of excel-
lence had to be ensured both in personnel and with respect to overall concep-
tion. The Society resolved to adopt,alongside its long-term program of institute
establishment, an immediate package of measures. It conceived of and financed
27 workshops for 5 years and thus alleviated the integration in institutes of
higher learning through additional project promotion.In addition, it set up two
temporary branches of Max Planck Institutes and took seven temporary focal
points of research in humanities into its care. Parallel to these immediate steps,
the MPS continued with the founding of new institutes.The qualitative and tem-
poral dimensions of the establishment program became a test of stress and
strain for the scientific committees.With the simultaneous construction and de-
construction that took place in the 1990s, the Max Planck Society underwent a
development that is also characteristic for a Germany that has enlarged its own
borders.The willingness of the federal government and the states to finance the
Society’s establishment program in full will result in enhanced research oppor-
tunities for the MPS.
2
The 1970s: The ‘First Genetic Revolution’ – and Germany?
The “age of biotechnology” started in the USA with the foundation of the first
biotech company. Genentech was founded by the renowned biochemist Herbert
Boyer and the young visionary venture capitalist Robert Swanson. (Of the
8 F. Hammar
people who worked there from the very beginning two were German scientists:
Axel Ulrich, now director at the Max Planck Institute for Biochemistry in

Martinsried, and Peter Seeburg, at present director at the Max Planck Institute
for Medical Research in Heidelberg.)
However, in Germany, everything progressed more slowly. Many scientists in
Germany regarded the field of recombinant DNA technology with skepticism
and did not foresee its potential. As a consequence, they concentrated on tradi-
tional techniques to study the basic mechanisms in genetics, cell and molecular
biology.
An example to the contrary, a researcher who worked at the forefront of mol-
ecular biology is Hartmut Hoffmann-Berling who in 1966 was appointed direc-
tor of the first Department of Molecular Biology at the Max Planck Institute for
Medical Research in Heidelberg. Hoffmann-Berling had performed pioneering
studies on ATP-driven cell motility during the 1950s, but switched to molecular
biology at the beginning of the 1960s after he discovered two new bacterial
viruses. Hoffmann-Berling concentrated initially on the characterization of
these bacteriophages, one of which was the first example of a rod-shaped, non-
lethal bacteriophage [33]. Between 1966 and 1974, he moved from the examina-
tion of viral self-assembly to the general processes of DNA replication. By the
mid-1970s, he had immersed himself into the search for individual components
of the multienzyme complex that is responsible for DNA synthesis. In 1976, he
discovered the first example of a DNA helicase [34–36]. Until his retirement in
1988, Hoffmann-Berling concentrated on unraveling the mechanisms by which
these ATP-driven motor proteins unwind the double helix during DNA synthe-
sis, repair damaged DNA and other related processes.
During the late 1960s and 1970s several other centers of excellence in the field
of molecular biology were established in Germany.
2.1
The Max Delbrück Center in Berlin-Buch
Berlin-Buch has a long tradition as a place for medical science, starting with the
foundation of the center at the turn of the century which temporarily comprised
hospitals with over 5000 beds. In 1928 the former Kaiser Wilhelm Society estab-

lished an Institute for Brain Research on what nowadays forms the Max
Delbrück Center’s (MDC) campus.
Later, the Academy of Sciences of the German Democratic Republic (GDR)
founded three research institutes in Berlin-Buch: one for Cancer Research, an-
other for Cardiovascular Research and a third one for Molecular Biology. In
1992, due to the German reunification, a new institution was developed from
these three institutes – the Max Delbrück Center. It is named after the Berlin-
born scientist Max Delbrück who strongly influenced the development of mol-
ecular biology.
Scientists of the MDC cooperate closely with clinicians of two specialized
hospitals in the vicinity: the Robert Rössle Cancer Clinic and the Franz Volhard
Clinic for Cardiovascular Disease. Both clinics form part of the Virchow
University Clinic, the Medical Faculty Charité of the Humboldt University of
History of Modern Genetics in Germany 9
Berlin. The close integration between basic and clinical research is aimed at
making new scientific findings available for patients as quickly as possible. The
MDC is a national research foundation. It obtains 90% of its funding from the
Federal Ministry of Education and Science, with the remaining 10% coming
from the state of Berlin.
2.2
The German Center for Cancer Research in Heidelberg
The German Center for Cancer Research (DKFZ – Deutsches Krebsforschungs-
zentrum) was founded in Heidelberg in 1964.As a non-profit organization it is
mainly funded by the Federal Ministry for Research and Education (90%) and
by the Ministry for Research and Sciences of the state of Baden-Württemberg
(10%). Additional funding is obtained from other public and private sources,
e.g. the German Science Organization (DFG – Deutsche Forschungsgemein-
schaft), special projects of the European Union (EU), of Federal and State min-
istries as well as cooperations with industry and private donations to the foun-
dation. Since 1975, it has been a National Research Center. Today, multidiscipli-

nary cancer research is performed by more than 50 divisions and working
groups with and without tenure. The majority of the division heads are ap-
pointed jointly with the University of Heidelberg. The Center’s research pro-
grams concentrate on cell differentiation and carcinogenesis,tumor cell regula-
tion, risk factors for cancer and prevention, diagnostics and experimental
therapy, radiological diagnostics and therapy, applied tumor virology, tumor
immunology,genome research and bioinformatics.
2.3
The European Molecular Biology Laboratory in Heidelberg
The European Molecular Biology Laboratory (EMBL) was established in 1974.
Fifteen countries from Western Europe and Israel support the Institution.It con-
sists of five facilities: the main laboratory in Heidelberg, and subsidiaries in
Hamburg (Germany), Grenoble (France), Hinxton (Great Britain) and Monte-
rontondo (Italy). The outstations provide European scientists access to large in-
struments for studying protein structure, some of the world’s oldest and largest
DNA and protein sequence databases and a broad range of services offered by
skilled biologists simultaneously working for their own research projects.
For most of them EMBL is a station en route. The scientific network created
by the people who once worked at EMBL and have now taken positions in other
countries has strongly contributed to the development of an international
scientific community throughout Europe.
In the late 1970s two young scientists took over their first independent re-
search positions at EMBL: Christiane Nüsslein-Volhard and Eric Wieschaus
joined their forces in order to identify the genes which control the early phase of
embryonic development in the fruit fly Drosophila melanogaster. They treated
the flies with mutagenic agents to produce random mutations in the Drosophila
genes.With a microscope they analyzed the embryos and classified a large num-
10 F. Hammar
ber of malformations due to mutations in genes controlling early embryonic de-
velopment. They were able to identify 15 different genes that caused defects in

segmentation if mutated. In 1980 they published their results in Nature and re-
ceived much attention from their colleagues [37]. In the years that followed de-
velopmental biologists were able to demonstrate that similar genes exist in
higher organisms and man, where they perform similar functions.
The pioneering work of Nüsslein-Volhard and Wieschaus and the studies on
the genetic basis of homeotic transformations in Drosophila performed by
Edward Lewis at the California Institute of Technology, Los Angeles, during the
1970s were honored with the Nobel Price in Physiology and Medicine in 1995.
Nüsslein-Volhard has dedicated a great part of her scientific life to the genes
of Drosophila. However, in her laboratory, molecular analysis was begun rather
late – in1986 – when she had been appointed director of an independent divi-
sion at the MPS for developmental biology in Tübingen. The first gap gene,
Krüppel, was cloned in the group of one of her colleagues, Herbert Jäckle [38].
3
The 1980s: Molecular Genetics Struggling Against Political Forces
During the 1980s natural sciences and technology faced a period of stagnation
in Germany.At this time in Germany it was not possible to establish a culture of
small companies, which are more flexible than large research institutions or big
companies and have a strong interest in the application of their results.One rea-
son was the attitude of many university researchers, who thought that science
had to be ‘pure’ and independent from financial considerations.A scientist who
directed his or her research interests according to economic benefit or the needs
of a customer – especially when this customer came from the powerful phar-
maceutical or chemical industry – was regarded with suspicion.
On the other hand, the environment for possible entrepreneurs was not very
friendly. Venture capitalists did not exist, public funding was oriented towards
academic research, and banks were not willing to finance these high-risk pro-
jects, often basing ‘only’ on an idea, the vision of the founding scientists. There
was a jungle of laws and regulations that had to be respected if one wanted to es-
tablish a new or enlarge an existing company.

As a result the first German biotechnology company Qiagen – now a world-
leading provider of technologies for separating and purifying nucleic acids –
had to move from Germany to the neighboring Netherlands to restructure the
company in preparation for the IPO.
Public opinion in Germany was adverse to science and technology; the anti-
nuclear movement and the emergence of the Green Party created a climate of
suspicion and fear towards applied scientific research and the related industries.
In particular, genetic engineering and molecular genetics were regarded as
damnable. The nightmare of genetically modified microorganisms escaping
from laboratories and killing half of the world population,or the awful vision of
an army of cloned super-soldiers, frightened many people in Germany. Of
course the technique was new and nobody was able to foresee all of its conse-
quences and possible risks, but a great part of the fear was due to a lack of in-
History of Modern Genetics in Germany 11
formation about the real risks and chances of the new technologies. The discus-
sion between opponents and supporters of gene technology was emotional and
demagogic instead of being objective and did not clear up the situation.With the
growing influence of the Green Party, the regulations for establishing a labora-
tory for molecular biology or a facility to work with recombinant technologies
became so strict that it was almost impossible for research institutions or in-
dustrial departments to expand further.A university institute that wanted to ap-
ply recombinant techniques had – for sensible reasons – to establish special
high-security laboratories. That was not only an expensive but also a time-con-
suming process due to the sluggish process of approval by regulatory authori-
ties.As a consequence, academic research had only limited possibilities to make
use of the novel methodologies, the development of the departments stagnated
and a whole generation of promising scientists left Germany to work abroad,
mostly in the USA,where they had better conditions to pursue their scientific in-
terests and the possibility to earn their living.
Industrial companies went the same way; they established new subsidiaries in

the USA and other parts of the world, and some even closed their research de-
partments in Germany. Instead of funding academic research in Germany,
German companies supported American universities. Hoechst, for example, a
West German chemical company, gave Massachusetts General Hospital,a teach-
ing facility of Harvard Medical School, 70 million $ to establish a new depart-
ment of molecular biology in return for exclusive rights to any patent licenses
that might emerge from the facility. Even today a deal of this kind would be ex-
tremely difficult to manage in Germany but in 1981 it was absolutely impossible.
3.1
Hoechst and Insulin – A Never-Ending Story
The company Hoechst provides another example of the difficulties a company
or institution encountered if it wanted to apply recombinant technologies in
Germany during the 1980s [39]. The controversy surrounding the official ap-
proval by the government of the German state Hessen has become a symbol for
the conflict between the German public, politics and gene technology.
Hoechst wanted to establish a plant for the production of recombinant in-
sulin on the company’s grounds in Hoechst near Frankfurt/Main. Hoechst was
already experienced in the production of insulin by isolating the hormone from
animal pancreas and now the company wanted to invent the recombinant
process to produce the human hormone, which is better tolerated by many pa-
tients than insulin from animals and acts in a more efficient way. The new plant
was to consist of three buildings: Fermtec for the fermentation, Chemtec for
isolating the crude product from bacteria and Insultec for the chromatographic
purification of the hormone.In 1984 Hoechst asked the local governmental au-
thority, the Regierungspräsidium in Darmstadt,for permission to build a plant
for the production of recombinant insulin. The request met unexpectedly ve-
hement opposition from the local public. People were afraid of genetically en-
gineered bacteria evading their fermenters and polluting the local environ-
ment.
12 F. Hammar

In spite of the protest the Regierungspräsidium gave the approval for the first
part of the plant, Fermtec, in 1985. Hoechst started the construction immedi-
ately. In 1986 the company applied for permission to construct the second part,
the Chemtec plant.In the meantime the Ministry for the Environment abolished
the license for the Fermtec plant. Nevertheless, the Chemtec plant was approved
in 1987.Local activist groups – arguing that there was no legal basis for the man-
ufacture of genetically engineered products – raised an objection to the con-
struction of both plants.In November 1987 both approvals were withdrawn and
Hoechst reacted by applying for immediate execution. In July 1989 the com-
pany’s petition was granted but 3 months later the opponents filed an applica-
tion to stop the immediate execution. The application was rejected in the first
court case but,in 1989,the opponents were successful with a second appeal. The
administrative court of the state of Hessen repealed the immediate execution.
Meanwhile the chief administrator in Darmstadt gave the permission to con-
struct the Insultec plant, the last phase of the construction. In spite of their ob-
jections the opponents were not able to stop the construction.On the first of July,
1990, the German Gentechnikgesetz (law regulating genetic engineering) came
into force. Although there were now legal rules for genetic engineering the op-
ponents managed to stop the production of insulin again.But this time it was the
company’s own fault. By deleting an unnecessary step of heat-inactivation
Hoechst changed the approved manufacturing protocol – without asking for the
permission of the approving authorities.The protest of a local citizens’initiative
was successful and Hoechst had to make an application to change the license in
1991. In 1994 the chief administrators in Darmstadt and Giessen finally ap-
proved the inauguration of the complete plant. However, during the years of
waiting, the scientists working at Hoechst had improved their methods.A novel
strain of E. coli was able to fold the protein correctly, a new plasmid had in-
creased the efficiency of the production process and environmentally beneficial
enzymatic steps replaced chemical ones. In 1996 Hoechst received approval for
the new procedure. Finally, in 1998, on the 16 March, the complete plant was

working for the first time. This date marks the endpoint of a frustrating quarrel
that, without doubt, set back Germany’s biotech and pharmaceutical industry.
4
The 1990s: A New Beginning – ‘The Second Genetic Revolution’
However, in spite of all the obstacles, German scientists at universities, medical
hospitals and research institutions were working with recombinant technolo-
gies. Many biochemistry departments completed their classical methodological
repertoire with cloning and sequencing techniques.Because DNA molecules are
relatively easy to handle – due to the simpler structure of nucleic acids com-
pared to the structure of proteins – kits for the different steps of DNA/RNA pu-
rification, for cloning and sequencing genes of interest were soon commercially
available. PCR became a standard method for medical diagnostics and biologi-
cal analysis.
Twenty years of gene technology without a serious accident have shown the
safety of the techniques if they are handled with care and sense of responsibil-
History of Modern Genetics in Germany 13
ity. Former opponents have grown older and regard the future perspectives of
molecular medicine from a different point of view. Genetic diagnosis has be-
come a standard tool: in Germany, for example, every pregnant woman over the
age of 35 can have an amniocentesis with subsequent chromosomal screen, un-
born infants from parents with inheritable disorders like cystic fibrosis can be
tested for the mutated gene in-utero and the first drugs and therapies developed
on the basis of molecular genetics research are available.
4.1
Developing a German Biotech Industry
Biotechnology for medical applications had become widely accepted and
recombinant methods were familiar to most scientists working in the field.
The first German biotech companies, the pioneers of the biotech industry
in Germany, Qiagen (established 1984), Rhein Biotech (established 1986),
MWG-Biotech (established 1990)and Evotec (established 1993), were strug-

gling along.
4.1.1
Qiagen – The Pioneer
During his doctoral thesis Metin Colpan, later cofounder and CEO of Qiagen,
had developed a new material based on anionic exchange for the isolation of nu-
cleic acids. He offered the new technology to several companies in the life sci-
ence industry,but nobody saw the necessity to use it.That was the reason for him
to found his own company in 1984. With the first Qiagen kit for purification of
plasmid DNA the time for preparing a plasmid could be reduced from 3 days to
2 hours. No wonder that the kit and its successors were eagerly accepted by in-
dustrial and academic researchers.Today Qiagen has become a market leader in
the field of isolation, purification and amplification of nucleic acids. By acquir-
ing a manufacturer of liquid-handling instruments,Qiagen has also entered into
the production of equipment. In addition the company offers services around
the purification of DNA on the industrial scale and acts as a partner in several
large genome-sequencing projects.
4.1.2
Rhein-Biotech – Becoming a Global Player
Rhein Biotech was founded in 1985 by Cornelis Hollenberg, head of the
Institute of Microbiology at the University of Düsseldorf, as he was no longer
able to manage his extensive contract research projects in his university insti-
tute. The young company used a patented expression system in yeast for the
production of recombinant proteins.Today Rhein-Biotech has become a global
player with subsidiaries in South America, Portugal, Africa, India and Korea
and is the third largest among the major manufacturers of vaccines for hepati-
tis B.Other products include proteins for the therapy of infectious diseases and
cancer [40–43].
14 F. Hammar
4.1.3
MWG-Biotech – An Instrumentation Supplier Develops into a Genomics Company

MWG started 1990 as a supplier of instrumentation and chemicals for molecu-
lar biology applications. Two years later they offered an additional service for
custom DNA synthesis and again one year later DNA sequencing completed
their services. Soon afterwards MWG started to develop instrumentation and
technologies on its own. The strategic concept to finance technological develop-
ment with the earnings of the services and the selling of instrumentation soon
turned out to be profitable.In 1999 MWG took measures to become a fully inte-
grated genomics company,able to address large genomics research projects [44],
and invested in the establishment of its own research department.
4.1.4
Evotec – Molecular Evolution for Drug Screening
Nobel laureate Manfred Eigen’s interest focused on the technological utilization
of ideas concerning evolution. By employing so-called evolution machines that
utilize the principles of biological evolution, new compounds can become opti-
mally adapted for particular functions.In the late 1980s/early 1990s,scientists in
Eigen’s laboratory developed methods to evolve not only self-replicating mole-
cules like RNA and DNA [45–47],but also proteins,particularly enzymes [48,49].
During a seminar, these results were discussed with Karsten Henco, who had
gained substantial experience in the biotech industry as a co-founder and
Managing Director of Qiagen. During this gathering the idea was born to start a
biotech company that would develop and commercialize products based on the
application of evolutionary technology. It was soon recognized that the selection
technologies developed for molecular evolution in the laboratory would also be
a perfect means to search for and select new potential pharmaceutical drug com-
pounds. Soon, Evotec evolved into what it is today: a drug discovery company. It
uses fluorescence correlation spectroscopy and related single-molecule detection
technologies and develops liquid-handling instrumentation and high-density
assay formats for automated miniaturized ultra-high performance screening.
4.2
The BioRegio Contest – Gambling for Success

Despite the activities of this handful of companies, Germany in the early 1990s
was still a wasteland for life science entrepreneurs.Oppressive regulations,a tra-
ditionally chemistry-driven pharmaceutical industry and lack of venture capi-
tal made Germany a tough place to start a biotech company.American and other
international investors were skeptical about providing capital for the founding
of a German biotech company. This situation changed abruptly when a politi-
cian had a somewhat strange idea: in 1996 Jürgen Rüttgers,then minister for re-
search and education, announced that he intended Germany to become the
number one in biotech in Europe by the year 2000. As a means to achieve this
goal he proclaimed the BioRegio contest. BioRegio should funnel money to the
History of Modern Genetics in Germany 15
three most promising biotechnology regions to support the growth of biotech
companies there. The three top regions were Munich, the Rhine-Neckar-
Triangle around Heidelberg and the area around Cologne. The former East-
German region Jena received a special acknowledgement.But even though only
three regions were awarded there were at least 17 winners because the contest re-
leased unexpected amounts of energy.All over the country,from Wilhelmshaven
in the north to Munich in the south, 17 Bioregions formed – even frontiers be-
tween the separate German states were no longer regarded as an obstacle. The
regions established networks to support prospective entrepreneurs with experi-
enced consultants, patent attorneys, and money. They established ‘incubators’,
buildings mostly located in the neighborhood of universities or research insti-
tutions, where young companies could rent laboratory space at fair prices and
get additional administrative support.Among life scientists at the universities –
from the youngest Ph.D. student up to the most venerable professor – it felt like
a ‘gold rush’. Even well-established industrial managers left their positions to
join the adventure – like Peter Stadler who had managed Bayer’s biotechnology
operations in Germany until he founded Artemis Pharmaceuticals, a target dis-
covery and validation company. The scientists at Artemis discover and explore
the function of individual genes in multiple experimental animals: due to the

scientific background of their co-founders, Christiane Nüsslein-Volhard,
Tübingen, and Klaus Rajewski, Cologne, they have access to zebrafish and mice;
their co-investor and collaboration partner Exilixis Pharmaceuticals in San
Francisco provides them with material from fruit flies and the worm C. elegans.
Money has flowed in from governmental funding programs, private funds of
the bioregions and venture capital companies became attracted by the emerging
biotech scene in Germany. Big companies who had formerly left Germany re-
turned and installed new departments or invested in cooperations with promis-
ing start-up companies. Jürgen Rüttger’s prophecy turned out to be right: in
1997 when Ernst & Young published the first German Biotech Report they
counted 23 big companies, 270 companies of medium size (more than 500 em-
ployees) and 123 small biotech companies [50].In 1998,when the fifth European
Life Science Report was published [51], this number had risen to 222 elevating
Germany to number two position behind Great Britain and in the seventh an-
nual European Life Sciences Report (2000) Germany has taken over pole posi-
tion with 279 biotech companies [52]. This is both a great success and also an
enormous challenge: now it has to be proved if the German model of encourag-
ing the formation of start-up companies will lead to a sustainable industry. As
the Report states: ‘Germany can now claim to be Europe’s most densely popu-
lated biotech kindergarten.’ It will certainly take some time to see if that in-
tensely nutured child finally reaches maturity.
4.3
Germany’s Contribution to the Human Genome Project and Other Genome Projects
Due to the further development of methodologies and technical equipment,the
focus of molecular genetics shifted from single genes to whole genomes. The
systematic analysis of complete genomes – the Human Genome Project – as well
16 F. Hammar
as initiatives to determine the total DNA sequence of several model organisms
like yeast [53], E. coli [54], the plant Arabidopsis thaliana [44,55], the nematode
Caenorhabditis elegans [56] or the fruit fly Drosophila [57] and pathogenic mi-

croorganisms,e.g. Plasmodium falciparum [58,59], the cause of malaria, should
provide new insights into the various aspects of the biology,pathology and evo-
lution of various organisms.The advancement of the instrumentation alone was
necessary but not sufficient for handling such large genome projects.Endeavors
of that scale demand the cooperative effort of many research groups and
German scientists were able to take their place in these international initiatives.
4.3.1
DHGP – German Human Genome Project
In June 1995, Germany joined the international efforts of the Human Genome
Project. The German Human Genome Project (DHGP) is funded by the German
Federal Ministry of Education and Research (BMBF) and the German Research
Organization (Deutsche Forschungsgemeinschaft – DFG).The initiative aims to
systematically identify and characterize the structure, function and regulation
of human genes, in particular those with medical relevance.
The comprehensive analysis of the human genome will give rise to a basic un-
derstanding of the function of the human organism. Due to the more detailed
knowledge about the molecular mechanisms,physicians will be able to improve
diagnostics and therapy. Between 1990 and 1998 more than 200 genes, that, if
mutated, are responsible for serious symptoms of disease, were identified. Of
special interest is the analysis of oncogenes and tumor suppressor genes; more-
over, genes which predispose a patient for developing diabetes,heart diseases or
Morbus Alzheimer are worthy of study. The significance of the Human Genome
Project goes far beyond the field of genetic diseases. The knowledge of all the
molecular elements of the human body will help the pharmaceutical industry to
find new targets for more effective substances and create the opportunity for an
individualized drug development. In addition it will make possible fundamen-
tally new approaches for therapy and diagnostics and, in many aspects, will
change our view of life.Therefore,special attention is also given to the ethical as-
pects of human genome studies.
The Resource Center at the Max Planck Institute for Molecular Genetics,

Berlin, and the German Cancer Research Center, Heidelberg, constitute the cen-
tral structural unit of the DGHP [60].It generates,collects and files standardized
reference materials and distributes them among all groups participating in the
DHGP [60].The extensive services of the center can also be accessed by other re-
searchers.Several research centers,34 research projects and 15 associated work-
ing groups spread all over the country are integrated parts of the initiative. The
high degree of integration,effective utilization of common resources and tightly
organized coordination is achieved by a scientific coordinating committee,con-
sisting of three elected members: Rudi Balling, Munich; Hans Lehrach, Berlin;
and Jens Reich, Berlin.
Research topics of the DGHP are bioinformatics, evolution, expression/gene
regulation, mapping/cytogenetics, model organisms and sequencing. Table 2
History of Modern Genetics in Germany 17
18 F. Hammar
Table 2. Research topics related to the German Human Genome Project. Source:

Research topic Group leader/coordinator
Bioinformatics
Bioinformatics of the human genome: W. Mewes, MPI for Biochemistry,
from ESTs to genes Martinsried
Computer-assisted editing of genomic sequences S. Suhai, DKFZ, Heidelberg
P. Levi, Stuttgart University
J. Reich, MDC, Berlin
A. Rosenthal, IMB, Jena
B.E.Wingender, GBF, Braunschweig
A new method for database searching and M.Vingron, DKFZ, Heidelberg
clustering
The Genome Computing Resource within DHGP S.Suhai, DKFZ, Heidelberg
MEDSEQ: Development of a service for J. Reich, MDC, Berlin
analysis of disease genes

Evolution
DNA-sequence evolution; mutation and S. Pääbo, MPI for Evolutionary
variation in the human genome Anthropology,Leipzig
Computer-assisted phylogenetic analysis A. von Haeseler,MPI for Evolutionary of
large genomic regions Anthropology,Leipzig
M.Vingron, DKFZ, Heidelberg
A comparative map of mouse, rat and Chinese J.Wienberg, National Cancer Institute,
hamster genomes by interspecies chromosome Frederick, MD, USA
painting; cross-species color segmenting –
a novel tool in human karyotype analysis
Comparative (Zoo-FISH) genome mapping T. Haaf, MPI for Molecular Genetics,
and positional cloning of evolutionary Berlin
chromosome breakpoints in important
mammal and vertebral genomes
Expression/gene regulation
Analysis of the transcription apparatus: I. Grummt, DKFZ, Heidelberg
from sequence to function E. Bautz, Heidelberg University
G. Peterson, Heidelberg University
DNA replication in large genomes: function of G. Feger, Serono Pharmaceutical
the human homologue of the MCM gene family Research Institute S.A., Plans.
Les-Ouates,Switzerland
W. Hemmer, GATC GmbH, Konstanz
Expressed RNA sequence tags (ERNs) J. Brosius, Münster University
in mouse brain
Functional analysis of independently regulated J. Bode, GBF, Braunschweig
transcription units: the human type I
interferon gene cluster as a paradigm
Generation of comprehensive libraries enriched A. Poustka, DKFZ, Heidelberg
for full-length cDNAs in the course of the S.Wiemann, DKFZ, Heidelberg
German Genome Project

Genomic sequencing of human zinc finger H J. Thiesen, Rostock University
gene clusters
History of Modern Genetics in Germany 19
Table 2 (continued)
Research topic Group leader/coordinator
Cloning and analysis of large genomic fragments T. Boehm, MPI for Immunobiology,
of pre-determined structure Freiburg
Alternative mRNA splicing: detection and A. Bindereif, Giessen University
analysis of human exonic enhancer sequences
using genomic SELEX
Structural and functional characterization of H. von Melchner, Frankfurt/Main
apoptosis induced genes University
Systematic characterization of protein-protein M.Meisterernst, E L. Winnacker,
interactions in man LMU Munich
Mapping/cytogenetics
Central Genotyping Service (GSU) at the Max F. Luft, Franz-Volhard-Klinik, Berlin
Delbrück Center E. Reis, MDC, Berlin
H. Schuster, Franz-Volhard-Klinik, Berlin
J. Reich, MDC, Berlin
K. Rohde,MDC, Berlin
T.Wienker, Bonn University
Theoretical and experimental analysis of J. Langowski, DKFZ, Heidelberg
chromatin three-dimensional structure and T. Cremer, LMU, Munich
internal motions P. Lichter, DKFZ, Heidelberg
E. Cremer,Heidelberg University
W. Jäger,Heidelberg University
Exon map in proximal Yq11 P.Vogt, Heidelberg University
Generation of sequence-ready maps of human A.Poustka, DKFZ, Heidelberg
chromosome 17p
Production and application of functional T. Cremer, LMU,Munich

defined DNA probes that can be amplified by
PCR for three-dimensional structural analysis
of chromosome territories
Nibrin, a novel DNA double-strand break repair K. Sperling,Virchow-Klinikum, Berlin
protein, is mutated in Nijmegen breakage
syndrome
Sequencing analysis of a 1.5-Mb contig in the A. Meindl, LMU, München
human Xp11.23 region A. Rosenthal, IMB, Jena
Cloning and characterization of the gene for S. Bähring, Franz-Volhard-Klinik, Berlin
hypertension and brachydactyly on the short A. Reis, MDC, Berlin
arm of chromosome 12 F. Luft, Franz-Volhard-Klinik, Berlin
Comparative physical and transcriptional I. Hangman, Halle University
mapping of human chromosome 20q13 R. Lilly,Marburg University
segment as candidate for imprinting T. Meeting, LMU, Munich
MITOP – the mitochondria project
Molecular analysis of the vertebrate genome H. Lehrach, MPI for Molecular Genetics,
Berlin
R. Setback, MPI for Molecular Genetics,
Berlin
M L.Yaps, MPI for Molecular Genetics,
Berlin
20 F. Hammar
Table 2 (continued)
Research topic Group leader/coordinator
Molecular characterization of the coding capac- M. Roche, Jena University
ity of the MHS4 region on chromosome 3q13.1 T. Duffel, Jena University
Systematic FISH mapping of disease-associated H H. Ropers,MPI for Molecular
balanced chromosome rearrangements (Debars) Genetics, Berlin
Multiplex-FISH (M-FISH): a multicolor method M. Speeches, LUM, Munich
for the screening of the integrity of a genome

Model organisms
The synapsis associated protein of 47 kD E. Buchner,Würzburg University
(SAP47): cloning and characterization of the
human gene and the function analysis in the
model system Drosophila
The immunoglobulin
k
locus of the mouse in H G. Zachau, LMU,Munich
comparison to the human
k
locus
Use of yeast artificial chromosomes (YACs) G.Schütz, DKFZ, Heidelberg
for transgenesis
Rat genome resource development and D. Ganten, MDC, Berlin
characterization M. Knoblauch, MPI for Molecular
Genetics, Berlin
H. Lehrach, MPI for Molecular Genetics,
Berlin
The ENU-mouse mutagenesis screen R. Balling, GSF, Oberschleissheim
M. Hrabe de Angelis, GSF,
Oberschleissheim
E.Wolf, LMU, München
From phenotype to gene: mapping of mutations R. Geisler, MPI for Developmental
in the zebrafish Biology, Tübingen
Isolation and characterization of monosomal H. Neitzel, Humboldt-University, Berlin
mouse cell lines and interspecific hybrid cells J. Klose, Humboldt-University, Berlin
with single mouse chromosomes M. Digweed, Humboldt-University,
Berlin
F. Theuring, Humboldt-University, Berlin
Systematic screen for novel genes required in B. Herrmann, MPI for Immunobiology,

pattern formation, organogenesis and differ- Freiburg
entiation processes of the mouse embryo
The zebrafish molecular anatomy project F. Bonhoeffer,MPI for Developmental
(ZMAP): towards the systematic analysis of Biology, Tübingen
cell-specific gene expression in the zebrafish,
Danio rerio
Functional analysis of mammalian genes by a W.Wurst, GSF, Oberschleissheim
large-scale gene trap approach in mouse H H.Arnold, Braunschweig University
embryonic stem cells E M. Füchtbauer, Aarhus University,
Danmark
H. von Melchner, Frankfurt University
Hospital
P. Ruiz, MPI for Molecular Genetics,
Berlin
not only shows the various aspects of research related to the human genome
project, it is also a small ‘who’s-who’ compendium of molecular genetics in
Germany to date.
4.3.1.1
Milestones
In May 2000, The Chromosome 21 Mapping and Sequencing Consortium, con-
sisting of researchers from Japan, Germany, England, France Switzerland and
the USA, reported a huge success: the completion of the sequence of chromo-
some 21 [61], the second finished human chromosome after chromosome 22
[62].However, only one month later,they were overtaken by US researcher Craig
Venter who announced that he had sequenced the whole human genome thereby
stepping into the post-genome age.
History of Modern Genetics in Germany 21
Table 2 (continued)
Research topic Group leader/coordinator
Systematic functional analysis and mapping of H. Jäckle, MPI for Biophysical

X-chromosomal genes in Drosophila melanogaster Chemistry, Göttingen
Sequencing
Sequencing of full-length cDNAs in the course S.Wiemann, DKFZ, Heidelberg
of the German Genome Project W.Ansorge, EMBL, Heidelberg
H. Blöckler, GBF, Braunschweig
H. Blum, LMU, Munich
A, Düsterhöft, Qiagen GmbH, Hilden
K. Köhrer, Düsseldorf University
W. Mewes, MPI for Biochemistry,
Martinsried
B, Obermaier, Medigenomix GmbH,
Martinsried
A. Poustka, DKFZ, Heidelberg
Towards sequencing of chromosome 21: Rosenthal, IMB, Jena
sequencing and automated annotation of 3 Mb H.H. Blöckler, GBF, Braunschweig
between AML-D21S17 and ETS-D12S349 H. Lehrach, MPI for Molecular
Genetics, Berlin
J. Ramser, MPI for Molecular Genetics,
Berlin
R. Reinhardt, MPI for Molecular
Genetics, Berlin
“Multiplex PCR sequencing”: an efficient way M. Hoehe, MPI for Molecular Genetics,
to analyze candidate gene variation Berlin
Comparative sequencing of a 1-Mb region in B. Zabel, University Hospital, Mainz
man (chromosome 11p15) and mouse A.Winterpacht,University Hospital,
(chromosome 7) Mainz
T. Hankeln, Mainz University
E. Schmidt, Mainz University
4.3.2
Microbial Genomes

Besides the Human Genome Project, Germany has taken part in several other –
especially microbial – genome projects. Since the reporting of the first complete
microbial sequence,the genome of the pathogen Haemophilus influenza in 1995
[63], by a group from The Institute of Genomic Research (TIGR), 36 microbial
genomes have been completely deciphered.These range from yeast and E. coli to
C. elegans and Drosophila, the most beloved pets of molecular biologists.
Figure 1 gives an overview of microbial genomes already sequenced.
These intensively studied organisms provide an invaluable possibility to cor-
relate genomic data to well-known biological functions.Genomes of pathogenic
microorganisms are also under investigation. Knowledge about their biology
and especially the mechanisms of their pathogenicity is necessary for develop-
ing therapeutic strategies to defeat them.German researchers from academic in-
stitutions or biotech companies have participated in sequencing Bacillus subtil-
lis, Mycoplasma pneumonia,andThermoplasma acidophilum [64–66].
Currently under investigation by German groups are Clostridium tetani, Me-
thanosarcina mazei, Thermus thermophilus (Göttingen Genomics Laboratory),
Corneybacterium glutamicum, Pasteurella haemolytica, Ustilago maydis (LION
Bioscience),and Halobacterium salinarium (MPI for Biochemistry, Martinsried).
The 6.1-Mb large genome of Pseudomonas putida is currently being studied
in a joint effort by a team of researchers from the USA and Germany. The US
22 F. Hammar
Fig. 1. Completely deciphered microbial genomes as of October 2000.Source: TIGR Microbial
Database, />partner is The Institute for Genomics Research (TIGR) in Rockville, MD. The
German consortium consists of groups from Hannover Medical School, DKFZ
Heidelberg, The Society for Biological Research (GBF), Braunschweig, and
Qiagen GmbH, Hilden. While the sequencing work is equally divided between
TIGR and Qiagen, the other groups carry out genome wide mapping and func-
tional analysis.Assembly and annotation are performed at TIGR.
The sequencing and the analysis of Dictyostelium discoideum, a soil-living
amoeba,is an international collaboration between the University of Cologne,the

Institute of Molecular Biology (IMB) in Jena, Baylor College of Medicine in
Houston, USA, the Pasteur Institute in Paris, France, and the Sanger Center in
Hinxton, England. Dictyostelium is an excellent organism for the study of the
molecular mechanisms of cell motility, signal transduction, cell-type differen-
tiation and developmental processes. Genes involved in any of these processes
can be knocked-out rapidly by targeted homologous recombination. The deter-
mination of the entire information content of the Dictyostelium genome will be
of great value to those working with this organism directly, as well as to those
who would like to determine the functions of homologous genes from other
species. The hereditary information is carried on six chromosomes with sizes
ranging from 4 to 7 Mb resulting in a total of about 34 Mb of DNA, a multicopy
90-kb extrachromosomal element that harbors the rRNA genes, and the 55-kb
mitochondrial genome.The estimated number of genes in the genome is 8000 to
10,000 and many of the known genes show a high degree of sequence similarity
to homologues in vertebrate species.
5
After 2000: Starting the Biological Age
One of the major goals in life sciences is now achieved: the complete sequence of
the human genome – for some people the ‘holy grail’ of molecular genetics – is
now available. The findings that were made during the 10 years of sequencing
the human genome as well as the results of other genome projects, including
model organisms and pathogenic microorganisms, are already revolutionizing
biology. Genome research provides a vital thrust to the increasing productivity
and persuasiveness of the life sciences.
However, some of the most challenging questions still remain. The sequence
of the genome is a static quantity: it provides a list of all the genes in a cell, but
it contains no information about their activity. Every single cell contains the
complete building plan for the whole organism, but it converts only a part of it
and differentiates into a skin, muscle or nerve cell. How are these complex
processes regulated and why does a cell develop in a distinctive way? These are

questions that cannot be settled by means of a genome analysis.
5.1
Beyond the Genome – Functional Genomics and Proteomics
Regulation of genetic activity and gene function are now the central points of in-
terest. Genetic diseases are rarely caused by the damage of one single gene.
History of Modern Genetics in Germany 23
Interactions between different genes – possibly located in spatial distance to
each other – can hardly be detected by analyzing the genome.
To test many of the approaches required for a comprehensive analysis of the
entire human genome, to systematically identify and analyze all human genes,
and to identify the medically interesting genes located there,a detailed investiga-
tion of certain regions on specific genes can be of great advantage. The X chro-
mosome is particularly interesting due to the large number of diseases that have
been associated with it.(Just remember the ‘classical’inherited disorders like he-
mophilia or color-blindness.) The telomeric part of the X chromosome, Xq27.3-
Xqter, is of interest due to the high gene density and the many diseases that have
been linked to this region. The systematic generation of physical and transcrip-
tion maps has facilitated the identification of many of the genes. Together with
extensive large-scale genomic sequencing this has led to the establishment of a
region-specific gene map with a very high resolution. The knowledge of the
methodologies and resources that was accumulated during this work has made
distal Xq into one of the best analyzed regions of the human genome.This region
can therefore be viewed as a model for the development and testing of strategies
for the large-scale identification of genes in the human genome and can now be
extended to the systematic functional and evolutionary analysis of genes.
Another focus which has become increasingly important with the progress in
technology has been directed at the identification and analysis of genes involved
in human cancer. It is obvious that the application of genome analysis tech-
niques is particularly important for cancer, since formation and progression of
tumors inherently involve large numbers of genes.

Understanding the molecular basis of psychiatric diseases is also a challeng-
ing task. The identification of genes responsible for such diseases can be a step
towards the comprehension of these complex disorders.
Only an analysis of the expression of mRNA molecules – which pass genomic
information on to the protein-synthesizing machinery – shows which genes are
really active in a certain cell of the body. Therefore, development of new auto-
mated techniques for displaying gene expression patterns and functional ge-
nomics, e.g. DNA chips and serial analysis of gene expression (SAGE), methods
for the introduction of macromolecules into living cells, the evaluation of gene
expression and their localization,through image acquisition and processing be-
come increasingly important.
High-throughput analysis of differential gene expression is becoming a pow-
erful tool with applications in molecular biology, cell biology, development, dif-
ferentiation and molecular medicine.The techniques that can be used to address
these questions are comparative expressed sequenced tag (EST) analyzing, full-
length cDNA sequencing, and SAGE and mRNA hybridization to cDNA or
oligonucleotide arrays on miniaturized DNA chips. These methods will help to
identify genes that are critical for a developmental process, genes that mediate
cellular responses to chemical or physical stimuli or to understand the molecu-
lar events affected by mutations in a gene of interest.In molecular medicine they
will serve for the identification of molecular markers for various disorders, and
in pharmacogenomics for the identification and characterization of drug targets
and of the molecular events associated with drug treatment.
24 F. Hammar